Etiopathogenesis of schizophrenia - the state of the art for 2021

Psychiatr. Pol. 2021; 55(2): 261–274
                         PL ISSN 0033-2674 (PRINT), ISSN 2391-5854 (ONLINE)
                                                         www.psychiatriapolska.pl
                                        DOI: https://doi.org/10.12740/PP/132953

           Etiopathogenesis of schizophrenia – the state
                       of the art for 2021

                                    Janusz Rybako ws k i

            Department of Adult Psychiatry, Poznań University of Medical Sciences

                                            Summary
      In 2021, one-hundred and ten years passed since a Swiss psychiatrist, Eugen Bleuler, in-
  troduced a term ‛schizophrenia’, denoting one of the most severe and stigmatizing psychiatric
  illnesses. Presently, it is known that the etiopathogenesis of schizophrenia is multifactorial,
  and a neurodevelopmental theory has been the most important pathogenic concept for more
  than 30 years. The theory postulates an interaction between genetic predisposition and envi-
  ronmental factors. In recent years, mainly thanks to employing the genome-wide association
  studies (GWASs), many molecular-genetic processes increasing a predisposition to schizo-
  phrenia have been identified. In the article, the role of pregnancy and perinatal period for risk
  of developing schizophrenia was considered. In patients with schizophrenia, as early as in
  childhood and adolescence, the disturbances of brain development occur, reflected, among
  others, by an impairment of cognitive functions. Childhood trauma makes a risk factor for
  developing schizophrenia and a less favorable course of the illness. The arising of the first
  psychotic episode is boosted by socio-environmental factors (e.g., migration, urbanicity) and
  psychoactive substance use, both increasing dopaminergic activity of the brain. In the paper,
  contemporary knowledge on the pathogenesis of psychotic and deficit symptoms and distur-
  bances of cognitive functions was presented. This was done concerning the neurotransmitters’
  changes and genetic and neuroimaging studies, with emerging therapeutic implications. At the
  end of the article, a current position of schizophrenia in the context of dichotomic division of
  mental disturbances put forward by Emil Kraepelin in 1899 was discussed.
     Key words: schizophrenia

                   Schizophrenia in psychiatry, Anno Domini 2021
    In 2021, the 110th anniversary is observed of coining by a Swiss psychiatrist,
Eugen Bleuler (1857-1939), the term “schizophrenia” [1]. Bleuler created this name
from two Greek words: “schizein” (split) and “phren” (mind). In his understand-
ing, it would denote an “inconsistency” of mental processes in this illness. The term
“schizophrenia” replaced the name “dementia praecox” (in Latin – early dementia)

262                                  Janusz Rybakowski

coined in 1899 by a German physician, Emil Kraepelin (1856-1926), for a chronic
illness with the early deterioration of cognitive functions [2]. As the basic symptoms
of schizophrenia, Bleuler suggested “four A’s” – i.e., autism, inappropriate affect,
ambivalence, and disturbances of thought association. However, several decades later,
a German psychiatrist, Kurt Schneider (1887-1967), as “the first rank symptoms of
schizophrenia” proposed psychotic symptoms, memorized in English as ABCD, where
A is Auditory hallucinations, B – Broadcasting of thought, C – Controlled thought,
and D – Delusional perception [3]. In the 1980s, clinical concepts of distinguishing
so-called positive (psychotic) and negative (deficit) symptoms occurring in the same
patient were put forward [4, 5]. It constituted some reconciliation of the views of
Kraepelin and Bleuler, favoring the symptoms of mental deficit (negative) and those
of Schneider who recognized psychotic (positive) symptoms as the main symptoms of
schizophrenia. In the last two decades a revival of interest in disturbances of cognitive
processes took place, presently recognized as the core symptoms of schizophrenia
which again makes a return to the “roots”, in other words, to Emil Kraepelin [6].
     The name “schizophrenia” has been used in the International Classification of Dis-
eases (ICD) and the American Diagnostic and Statistical Manual for Mental Disorders
(DSM) since their beginning. In both classifications, similar although not identical
kinds of the illness have been delineated [7, 8]. However, in the most recent edition
of DSM-5, the subtypes of schizophrenia were not distinguished [9]. An attempt to
destigmatize the name “schizophrenia” was made by Japanese psychiatrists. In 2002,
in Japan, the name Seishin Bunretsu Byo (split mind disease) was changed into Togo
Shitcho Sho (integration disorder) [10].
     Therefore, at the beginning of the third decade of the 21st century, in the illness
called “schizophrenia”, three groups of clinical symptoms can be distinguished, namely
psychotic and deficit symptoms as well as disorders of cognitive functions. Since the
1960s, the pathogenetic studies have concerned mainly psychotic symptoms primarily
because of the introduction of their effective treatment in the early 1950s [11]. The re-
search on deficit symptoms and cognitive dysfunctions was significantly intensified in
the 1990s. Presently, it is widely accepted that the etiopathogenesis of schizophrenia
is multifactorial, and a neurodevelopmental theory has remained the most important
pathogenetic concept for more than 30 years. Its quintessence assumes that in patients
with schizophrenia, a genetic predisposition to the illness occurs and an impairment of
brain development determined by various factors of the prenatal, perinatal, and early
period of life until adolescence takes place. This results in the brain being more vulner-
able to stress factors acting in adolescence and early adulthood, such as environmental
factors and psychoactive substance use. In consequence, this leads to a clinical appear-
ance of the illness, usually in the form of the first psychotic episode. Such a hypothesis
was independently formulated in 1987 by a British psychiatrist, Robin Murray, and
an American psychiatrist, Daniel Weinberger [12, 13]. On the 30th anniversary of this
idea, both researchers published articles on this subject in the “Schizophrenia Bulletin”
in which they confirmed its scientific foundation. In his publication, Daniel Weinberger
discusses in detail the most recent genetic and epigenetic data about this concept [14].
On the other hand, Robin Murray focuses mostly on environmental factors precipitating

Etiopathogenesis of schizophrenia – the state of the art for 2021        263

the first psychotic episode of schizophrenia. According to him, the neurodevelopment
hypothesis of schizophrenia can be nowadays defined as the developmental risk factor
model of psychosis [15].
     In this paper, the current status of the verification of the elements of the neuro-
developmental theory of schizophrenia will be discussed. The contemporary data on
the pathogenesis of psychotic and deficit symptoms, as well as cognitive dysfuntions
in schizophrenia will also be presented, mainly in the context of changes in neuro-
transmitter systems and the resulting therapeutic implications. At the end of the article,
a current position of schizophrenia against the backdrop of dichotomic division of
mental disturbances into “dementia praecox” and “manisch-depressives Irresein” put
forward by Emil Kraepelin in 1899 will be discussed [2].

                            Genetic factors of schizophrenia
     An essential component of the “genetic” part of the neurodevelopmental theory is
showing that many genes connected with a predisposition to schizophrenia can influ-
ence the early period of brain development, brain maturation, and the differentiation
of nerve cells. In the field of molecular genetics, the neurodevelopmental concept of
schizophrenia found its first confirmation in 2002, when in the research of the Icelandic
population, an association with a predisposition to schizophrenia was demonstrated
for the neuregulin 1 (NRG1) gene, located on chromosome 8p12 and connected with
the processes of brain development [16]. A year earlier, a paper was published where,
based on the analysis of chromosome 1 translocation in a Scottish family with multiple
cases of schizophrenia, a gene Disrupted in Schizophrenia 1 (DISC1), located on 1q42
was identified as predisposing to schizophrenia [17]. Further studies showed that the
protein coded by the gene plays an important role in the development and maturation
of the brain as well as in the differentiation and proliferation of neurons [18].
     For more than a decade, the genome-wide association studies (GWASs) allowing
to identify several millions of polymorphisms of the whole genome’s genes have made
the forefront of genetic research. In the GWAS study performed in 2008, an association
with schizophrenia was demonstrated for the zinc finger protein 804 (ZNF804) gene
located on chromosome 2q32 [19], whereas a paper from 2009 indicated a connection
between a predisposition to schizophrenia and the region of the Major Histocompat-
ibility Complex (MHC) located on chromosome 6p21 [20]. Both these findings were
replicated in subsequent GWAS studies.
     The most important molecular-genetic research of schizophrenia using the GWAS
approach was published in the journal Nature in 2014. The study included 37 thousand
schizophrenia patients and 133 thousand healthy persons, and demonstrated the associa-
tion with schizophrenia for the polymorphisms of 108 genes. Among them are found
the dopaminergic receptor D2 (DRD2) gene, the genes of the glutamatergic system
and tissue plasticity (GRM3, GRIN2A, GRIA1, SRR) and the genes of calcium chan-
nel subunits (CACNA1C, CACNA1I, CACNB2) [21]. In the context of the polygenic
pathogenesis of schizophrenia, each of these genes can contribute to less than 1% of
the effect on the occurrence of the illness.

264                                 Janusz Rybakowski

     In many GWAS studies, microscopic chromosomal aberrations resulting in the
variations of genome fragments, i.e., copy number variations (CNVs) in schizophrenia
patients were found. They were demonstrated in many genome areas, most frequently
in the regions of chromosomes 1q21, 15q11, and 22q11 [22, 23]. These aberrations
play a disrupting role in brain development during the fetal period and early childhood.
Besides schizophrenia, they occur, even to a greater extent, in such neurodevelopmental
disorders as autism and intellectual disability. Therefore, given the presence of CNVs,
schizophrenia can be genetically related to the neurodevelopmental disorders mentioned
above. Studies on the deletion of the above mentioned region 22q11.2, where many
genes are located, e.g., the catechol-O-methyltransferase (COMT) gene, showed that
this abnormality increases the risk of schizophrenia 25-fold [24].
     Contemporary research also shows that a predisposition to schizophrenia shares
common genetic elements with other psychiatric illnesses, mainly with bipolar affective
disorder. In 2009, Swedish researchers analyzing more than 2 million families showed
a genetic overlap between schizophrenia and bipolar affective illness: the first-degree
relatives of individuals with either schizophrenia or bipolar disorder had an increased
risk for both these illnesses [25]. In the GWAS study, common genes for schizophrenia,
bipolar disorder, and several other psychiatric disorders were demonstrated [26]. Nev-
ertheless, a large group of genes characteristic for schizophrenia has been identified,
whose combination represents the polygenic risk score for schizophrenia (PRSS). This
score has been widely used in research, aiming to demonstrate its relationship with
clinical parameters or response to pharmacological treatment [27].
     In schizophrenia, epigenetic changes are also present, such as abnormal DNA
methylation and histone modification which can modulate gene expression without
influencing the genome structure. These changes constitute a mediating mechanism for
environmental factors in the early period of life and may play a role in leading to the
first psychotic episode [28]. Among new research methods, whole exome-sequencing
analysis may be of interest. The exome is a collection of all the exons, i.e., the pieces
of a gene coding the amino acid sequence in a protein molecule. Using this method,
a loss of function of the SETD1A gene was demontrated. This gene is located on chro-
mosome 16p11 and is coding methylation of the amino acid lysine. Its loss of function
was found not only in schizophrenia but also in such neurodevelopmental disorders
as intellectual disability and epilepsy [29].
     As related to genetics, clinical research can be recognized in which an increased
risk of schizophrenia with higher paternal age was demonstrated. It can be explained
by a growing number of de novo mutations in male germ cells with age [30].

          Pregnancy and the perinatal period and risk of schizophrenia
    An important element of the neurodevelopmental hypothesis of schizophrenia is
an assumption that the factors acting during pregnancy and the perinatal period can
exert an effect on the development of the illness. Cannon et al. [31], on the basis of
a meta-analysis of 20th-century publications, listed three groups of factors increasing
the risk of schizophrenia: (1) complications of pregnancy (bleeding, diabetes, Rh

Etiopathogenesis of schizophrenia – the state of the art for 2021      265

incompatibility, preeclampsia); (2) abnormal fetal development (congenital malforma-
tion, low birth weight, reduced head circumference); and (3) complications of delivery
(asphyxia, uterine atony, emergency Cesarean section). Polish researchers comparing
50 patients with a first psychotic episode and 50 matched healthy persons found an as-
sociation between obstetric complications and lower Apgar score and subsequent risk
of developing psychosis [32].
     The most significant pathogenic factors of pregnancy and the perinatal period in-
creasing the predisposition to schizophrenia include fetal malnutrition, preterm birth,
asphyxia, and infections. Concerning infections during pregnancy, in many studies
the role of influenza infection, mainly in the first trimester, has been demonstrated.
The second microbe with the most evidence regarding this issue is a protozoan, Toxo-
plasma gondii. The data on the significance of Herpes simplex virus type 2 (HSV-2)
is still controversial. The mechanism of brain damage as a vector of susceptibility to
schizophrenia is connected with abnormal activation of the immune system. In the
mothers of schizophrenic patients, significantly elevated levels of pro-inflammatory
cytokines were observed during pregnancy and the perinatal periods. It was also found
that the immunological activation was propped up by a genetic predisposition, among
others the NRG1 and DISC1 genes [33].

          Deterioration of cognitive functions and brain development
                             in the early life period
     The Kraepelinian concept of “dementia praecox” assumes an impairment of cogni-
tive functions at the early stage of the illness. However, the evidence exists nowadays
indicating that a disturbance of brain development resulting in an impairment of cog-
nitive functions can precede the appearance of the first episode of schizophrenia by
many years [34]. The studies performed in the last two decades show an intellectual
deficit during adolescence in persons who later develop schizophrenia [35].
     In patients with schizophrenia, the disturbances of brain development are already
present in childhood, and during adolescence lead to abnormalities in synaptic “prun-
ing” in the prefrontal and temporal cortex. “Pruning” means the elimination of un-
necessary synaptic connections. In patients with schizophrenia, this phenomenon is
excessive and results in a reduction of the number of postsynaptic elements in these
brain structures [36]. It is one of the most important causes connected with a progres-
sive cognitive deficit before the first psychotic episode.
     Many genes associated with a predisposition to schizophrenia are located on the
HLA complex on chromosome 6p21. Among them, there is the complement compo-
nent 4 (C4) gene. In patients with schizophrenia, a preponderance of the gene’s allele
connected with increasing activity of this component was found. Since in mice this
gene plays a role in the elimination of synapses during the early postnatal period,
a hypothesis was proposed that in patients with schizophrenia it can be connected with
excessive synaptic pruning during adolescence [37].
     The evidence for brain function abnormalities obtained from studies of the first-
episode schizophrenic patients indicates that they are not due to a progression of

266                                  Janusz Rybakowski

the illness or pharmacological treatment. Already during this time, in patients with
schizophrenia, the disturbances of interneuronal connections (connectome) of the
brain occur. Such disruptions of white matter connections, especially in the prefrontal
and temporal cortex, were found by Dutch investigators, both in patients, where they
correlated with cognitive impairment and in their first-degree relatives [38, 39]. In
such patients, a disrupted synchronization of neural oscillations is also demonstrated,
corresponding with cognitive deficits [40].

             Childhood trauma in the pathogenesis of schizophrenia
    The experience of early childhood trauma can influence the future risk of occur-
rence and course of schizophrenia. A pioneering study on this subject was published in
1999 when Israeli researchers showed that parental loss, mostly before 9 years of age,
increases the risk of schizophrenia by 3.8-fold [41]. In the 21st century, there has been
dynamic research progress on this topic. The possible neurobiological mechanisms
have been indicated by which the negative early childhood experiences increase the
probability of schizophrenia and its less favorable course. Childhood trauma consti-
tutes a severe stress event, resulting in activation of the hypothalamic-pituitary-adrenal
axis and a sensitization of the dopaminergic system, precipitating the first psychotic
episode of schizophrenia [42]. Besides the stress axis disturbances, as a consequence
of negative childhood experiences, disturbances of brain development and cognitive
dysfunctions occur. In their inception, a genetic predisposition and epigenetic factors
play a significant role [43].

      The factors precipitating the first psychotic episode of schizophrenia
     In recent decades, two important groups of factors were identified which pre-
cipitate the occurrence of the first psychotic episode of schizophrenia. The common
final effect of their action likely causes an increase of the brain dopaminergic system
activity [44]. The first category includes socio-environmental factors such as, among
others, migration and urbanicity. A recent meta-analysis of the impact of the migration
process performed by Bourque et al. [45] showed that the risk for psychotic disorders,
mainly schizophrenia, in the first-generation immigrants was 2.3-fold higher than in
the country of origin, and in the second generation – 2.1-fold higher. Irish research-
ers based on the literature review and prospective studies in Ireland stated that living
in big cities, compared with rural areas, increased the risk of schizophrenia 2-fold in
males and 1.34-fold in females [46]. The second group of factors is of biological or,
strictly speaking, pharmacological character and involves the use of psychoactive
substances. The effect of the use of such psychostimulants as amphetamine or cocaine
on schizoprenia risk has been repeatedly confirmed [47]. However, in recent years,
a possibility of inducing the first episode of schizophrenia by chronic cannabinoid use
has been pointed out [48].
     Recently, Guloksuz et al. [49] investigated the interaction of genetic and environ-
mental factors employing the polygenic risk score for schizophrenia (PRSS). They

Etiopathogenesis of schizophrenia – the state of the art for 2021       267

showed an additive interaction between the PRSS and childhood trauma and chronic
cannabinoid use.

The pathogenesis of psychotic and deficit symptoms and cognitive dysfunctions
     The majority of information on the pathogenesis of the groups of symptoms of
schizophrenia has been connected with changes of neurotransmitter systems. Fre-
quently, it has been supported with genetic and neuroimaging data. In some studies,
certain common mechanisms of deficit symptoms and cognitive dysfunctions have
been indicated. The data connected with neurotransmitters bear the pharmacothera-
peutic implications.
     The most important for the theory of pathogenesis and the practice of schizophre-
nia treatment has been the dopaminergic system of the brain. The discovery of the role
of this system in the mechanism of action of antipsychotic drugs in the 1960s [50]
resulted in the development of the “dopaminergic” pathogenetic concept of psychotic
symptoms. Nowadays, it is thought that in the generation of psychotic symptoms (also
known as “positive”) a crucial role is played by the hyperactivity of dopaminergic
subcortical structures, mainly those of the striatum [51]. In a neuroimaging study,
in patients with an exacerbation of schizophrenia, increased amphetamine-induced
release of dopamine in the striatum was demonstrated, which correlated with the
severity of positive symptoms [52]. A probable mechanism of dopaminergic dys-
function in schizophrenia is increased presynaptic dopamine synthesis which results
in its excessive release [53]. The neuropsychological concept regarding the role of
dopamine in the generation of psychotic symptoms assumes the importance of this
neurotransmitter for the assessment of the salience of the stimuli. Dopaminergic
hyperactivity causes that all stimuli, independently of their meaning, are assessed as
salient which leads to information overload of the brain. Psychotic symptoms such
as delusions and hallucinations are produced as a result of an adaptative reaction of
the brain to such a situation [54].
     So far, all antipsychotic drugs used in the treatment of schizophrenia act on the
dopaminergic system. Mostly, they exert an antidopaminergic effect by blocking the
D2/D3 receptors. This applies to both classical and atypical antipsychotic drugs [55].
As previously mentioned, the dopaminergic receptor DRD2 gene was identified in the
GWAS as connected with a predisposition to schizophrenia [21]. In the treatment of
schizophrenia, the partial agonists of D2/D3 receptors have also been employed such as
aripiprazole, brexiprazole, and cariprazine [56], and recently, lumateperone was added
here [57]. In the therapeutic mechanism of the atypical antipsychotic drugs and partial
agonists of dopaminergic receptors, a significant role is played by their concomitant
action on serotonergic receptors.
     The dopaminergic system also plays an important role in the pathogenesis of deficit
(negative) symptoms and impairment of cognitive functions in schizophrenia. Dopa-
minergic hypoactivity, especially of dopaminergic type 1 receptors in the prefrontal
cortex, has proved significant here [58]. In the pathogenesis of negative symptoms,
besides diminished prefrontal function of DRD1, reduced dopaminergic activity in the

268                                  Janusz Rybakowski

caudate nucleus has also been postulated [59]. In a neuroimaging study, a deficit of
dopamine release in the dorsolateral prefrontal cortex was observed, and its severity
correlated with impairment of working memory [60]. For a therapeutic effect for nega-
tive symptoms, the stimulation of the cortical dopaminergic system can be obtained
by dopamine autoreceptor blockade (amisulpride), agonistic action on dopamine D2/
D3 receptors (aripiprazole, brexiprazole, cariprazine), and by inhibiting serotonergic
5-HT2 receptors (a majority of the atypical antipsychotic drugs).
     A possible pathogenic role of serotonin in schizophrenia was considered as early
as in the 1950s when it was discovered that a psychomimetic substance – lysergic
acid diethylamide (LSD) – influences the serotonergic system. [61]. More than 60
years of further studies revealed that the most important in this respect are serotonin
5-HT2A receptors, playing a significant role both in the brain development as well as
in a predisposition to schizophrenia [62]. In genetic studies, the association of the poly-
morphism of the 5-HT2A gene with neurophysiological disturbances in schizophrenia
[63] as well as the abnormal methylation of this gene in the illness [64] were found.
The blocking of 5-HT2A receptors in the prefrontal cortex can increase the activity
of the dopaminergic system in this brain structure. It may be important for the action
of the atypical antipsychotic drugs and their possible effect on deficit symptoms and
cognitive dysfunctions in schizophrenia [65]. Recently, attention has also been paid
to the serotonergic receptors 5-HT6 and 5-HT7, and a possibility of application of the
therapeutic action on these receptors [66].
     As already mentioned, in the mechanism of action of atypical antipsychotics and
partial agonists of dopaminergic receptors, there is a combination of their effect on
the dopaminergic (D2/D3 receptors) and serotonergic systems (5-HT2A and 5-HT1A
receptors). However, as to the antipsychotic action of the “pure” serotonergic drugs, the
most data have been accumulated for pimavanserin, a reverse agonist of the serotoner-
gic 5-HT2A receptor. The therapeutic action of pimavanserin has been demonstrated
in Parkinson’s disease psychosis, and some attempts of using it in schizophrenia have
also been undertaken [67].
     In the mid-1990s, a glutamatergic hypothesis of schizophrenia was formulated,
postulating a decrease in the activity of the glutamatergic N-methyl-D-aspartate
(NMDA) receptor in this illness [68]. In further years, ketamine, a substance acting
antagonistically on the NMDA receptor, served for creating a model of schizophrenia
presenting psychotic, deficit, and cognitive symptoms [69], and the role of the gluta-
matergic system in a predisposition to schizophrenia has been confirmed in numerous
molecular-genetic studies [70]. The glutamatergic system is important for the devel-
opment of the brain. In this process, a dysfunction of NMDA receptors on GABA-
ergic neurons takes place in the early period of life [71], and the epigenetic changes
of the glutamatergic system genes can be contributing factors [72]. As a therapeutic
implication of the glutamatergic system changes in schizophrenia, attempts of using
so-called inhibitors of the glycine site, a part of the NMDA receptor, for augmentation
of antipsychotic drugs in the treatment of negative symptoms were made [73]. On the
other hand, despite an initial promise, the antipsychotic action of the metabotropic
glutamatergic receptor type 2/3 has eventually not been confirmed [74].

Etiopathogenesis of schizophrenia – the state of the art for 2021          269

    As to the pathogenesis of cognitive dysfunctions in schizophrenia, a paper should
be noted, suggesting the foundation of the generalized cognitive deficit in this illness
as a dysfunction of the cortico-cerebellar-striatal-thalamic loop and task-positive and
task-negative cortical networks [75]. It is also worthwhile to mention the results of
a recent genetic study indicating a correlation between cognitive dysfunction and the
magnitude of the CNV changes [76].

         Schizophrenia and the dichotomic division of mental disorders
                              by Emil Kraepelin
     In 2019, the 120th anniversary of the fundamental concept of the division of men-
tal disorders by Emil Kraepelin into “dementia praecox” and “manisch-depressives
Irresein” was observed [2]. As mentioned, the name “dementia praecox” was re-
placed by Eugen Bleuler by the term schizophrenia, and the closest equivalent for
“manisch-depressives Irresein” is presently bipolar affective disorder. In a clinical
sense, Kraepelin’s dichotomic idea was undermined as early as in 1933, when Jacob
Kasanin introduced the term schizoaffective psychosis [77]. After more than 50 years
from this event, Timothy Crow placed this psychosis in the middle of the proposed
continuum of psychiatric disorders [78]. On the neurobiological ground, a significant
questioning of Kraepelin’s division took place in the 1990s when it was found that
there is a remarkable overlap of genes predisposing to schizophrenia and bipolar
disorder and that atypical antipsychotic drugs are therapeutically effective in both
these illnesses. However, in the context of the neurodevelopmental theory of schizo-
phrenia, some neurobiological distinctiveness from bipolar disorder can be observed
in many areas. It has been demonstrated that schizophrenia patients are affected by
more factors impeding brain development and are particularly susceptible to them.
In the genome of schizophrenia subjects, there are more CNV changes, and infectious
factors occurring during pregnancy, perinatal traumas, certain socio-environmental
factors as well as psychoactive substance abuse are of greater significance in this
illness. A modified neurodevelopmental concept of schizophrenia considers these
factors as a so-called “second hit” superimposing on a genetic predisposition. As
a result, patients with schizophrenia during the first psychotic episode present more
intensified neuroanatomical changes and cognitive function disturbances, compared
to patients with bipolar disorder [79].
     In conclusion, in the context of a discussion about the current topicality of Kraepe-
lin’s concept, it seems that his dichotomy still retains certain merit.

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      Address: Janusz Rybakowski
      Poznan University of Medical Sciences
      Department of Adult Psychiatry
      60-572 Poznań, Szpitalna Street 27/33
      e-mail: janusz.rybakowski@gmail.com